Multiple inhibitory molecules create a profoundly immunuosuppressive environment that is conserved among chronic viral infections and makes eliciting effective immunity challenging. Human persistent viruses highly relevant to health, including HIV, HCV and HBV are restricted to human and non- human primates, which poses great limitations and difficulties to experimental based research. The complexity of the immune system cannot be accurately recreated in vitro and its study requires the use of appropriate whole organisms. We have therefore chosen to use chronic lymphocytic choriomeningitis virus (LCMV) infection of its natural host, the mouse, as a model system. In a previous study, we found that interleukin-6 (IL- 6) is produced in a unique biphasic manner during persistent LCMV infection and that late IL-6 escalates T follicular helper responses, being essential for viral control (Harker et al. Science 2011). IL6 shares the transducing co-receptor gp130 with the IL6 family of cytokines of which four have been related to the immune system. Our preliminary studies indicate that ablation of gp130 in T cells during chronic LCMV infection resulted in more profound defects than the sole absence of IL6 signaling, as indicated by reduction of virus-specific CD4 T cell numbers and their IL-21 secretion (in addition) to diminished Tfh responses. These data indicate that gp130 signaling cytokines, including but not limited to IL6, play a central role in orchestrating CD4 T cells responses and resolving persistent LCMV infection in vivo. We propose to investigate the role of gp130 signaling cytokines (other than IL-6) and their mechanistic link to CD4 T cell responses during chronic LCMV infection. In Aim #1 we will study gp130flox/flox mice to investigate the role of gp130 signaling at different times and in specific cell populations during chronic LCMV infection. We will determine the mechanism underlying gp130 control of CD4 T cell numbers by measuring survival and proliferation in mixed bone marrow chimeras. In Aim 2 we will explore the levels of and CD4 T cell responsiveness to gp130-cytokines (other than IL6) and we will use shRNA and/or genetically modified mice to investigate their function during chronic LCMV infection. Studies in the past three decades using LCMV murine infection have demonstrated high conservation in the immune responses against persistent viruses in mouse and humans. Therefore the knowledge gained from the proposed experiments will not only enhance our understanding of basic immunology but also point out important players that could regulate immune responses and represent therapeutic targets during chronic viral infections in humans. Furthermore, since LCMV is considered a prototypic arenavirus the proposed studies will increase our understanding of the pathogenesis of human arenaviruses, which cause fatal hemorrhagic fevers. PUBLIC HEALTH RELEVANCE: Chronic viral diseases represent a major biomedical problem. One limitation to fight off persistent viruses is the limited knowledge on the molecules that could promote immunity in the context of the profound inhibitory environment that characterizes chronic viral infections. We have identified a signaling pathway that effectively promotes adaptive immune responses in a murine model infection. We propose to study the cellular and molecular mechanisms involved and how to harness this pathway to prevent or attenuate viral persistence. !